Valsartan is chemically known as N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-valine. Valsartan is a non-peptide AT1-subtype angiotensin II receptor antagonist. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. Valsartan is used for the treatment of hypertension and is marketed as the free acid under the brand name DIOVAN®.
Valsartan and its pharmaceutically acceptable salts are disclosed in U.S. Pat. No. 5,399,578.
According to U.S. Pat. No. 5,399,578, the process for the preparation of Valsartan (I) involves the reaction of 4′-bromomethyl-2-cyanobiphenyl (II) with sodium acetate and glacial acetic acid to produce 2′-cyano-4-hydroxymethylbiphenyl (III), which is reacted with oxalyl chloride in dichloromethane and dimethyl sulfoxide to produce 2′-cyano-4-formylbiphenyl (IV), which is further reacted with (L)-valine methyl ester hydrochloride (V) and sodium cyanoborohydride to produce N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VI), followed by treatment with valeryl chloride to produce N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII), which is treated with tri-n-butyltin azide followed by flash chromatography to produce Valsartan of formula (I).
The process is as shown in Scheme-I below:

The major disadvantage with the above process is the use of triethylamine in the process for the preparation of the compound of formula (VII), in which process, the reaction is incomplete due to the presence of moisture, affecting the quality of the product, leading to a lower yield and requires flash chromatography for purification. Conversion of the compound of formula (VII) to Valsartan also involves flash chromatography. Employing column chromatography technique is tedious and laborious and also involves use of large quantities of solvents, and hence is not suitable for industrial scale operations.
Bioorganic & Medicinal Chemistry Letters (1994), 4(1), 29-34, reported a process for the preparation of Valsartan by reacting 4′-bromomethyl-2-cyanobiphenyl (II) with (L)-valine methyl ester hydrochloride (V) in the presence of diisopropylethylamine in methylenechloride to produce N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VI), followed by reacting with valeryl chloride in the presence of diisopropylethylamine in methylenechloride to produce N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII), which is further reacted with tributyltin azide in xylene to produce N-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-N-valeryl-(L)-valine methyl ester (VIII), followed by hydrolysis with aqueous base to produce Valsartan of formula (I).
The process is as shown in Scheme-II below:

According to the process reported in IP. Com Journal (2006), 6(7B), 23, No. IPCOM000138267D, N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII) is produced by condensing N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VI) with valeryl chloride in the presence of potassium carbonate in xylene.
U.S. Pat. No. 7,659,406 B2 discloses a process for the condensation of N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VI) or a salt thereof, with valeryl chloride in the presence of an inorganic base in a solvent to produce N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII).
The above processes involve the condensation of halomethylbiphenyl derivative with L-valine ester is one of the important steps for the synthesis of Valsartan. It was observed that the condensation of compound of formula (II) with L-valine ester of formula (V) generates about 5% unwanted dimeric impurity of formula (VIa) along with desired compound of formula (VI). This impurity in turn is carried forward in subsequent reaction steps and results in Valsartan (I) with the undesired impurity of formula (Ia) This results in the poor yield and quality of the Valsartan product and requires additional purification step.

It was also observed with the prior-art processes, that the condensation of compound of formula (VI) with n-valeroyl chloride resulted about 2% unwanted alkene impurity of formula (VIIa) along with desired compound of formula (VII). This impurity in turn is carried forward in subsequent reaction steps and results in Valsartan (I) with the undesired impurity of formula (Ib). This results in the poor yield and quality of the Valsartan product and requires additional purification step.

Further, it was observed that the formation of thermal degradation impurity of formula (VIIIa), which was formed during the conversion of compound of formula (VII) to compound of formula (VIIIb). This impurity in turn is carried forward in subsequent reaction steps and results in Valsartan (I) with the undesired impurity of formula (Ic). This results in the poor yield and quality of the Valsartan product and requires additional purification step.

Hence, there is a need to have simple, easy to handle and cost effective process for the preparation of Valsartan and its intermediates with high chemical purity and optical purity.
The present invention is specifically directed towards the process for the preparation of intermediate compounds of formulae (VI), (VII) and (VIIIb), which are substantially free from their dimeric impurity of formula (VIa), alkene impurity of formula (VIIa) and thermal degradation impurity of formula (VIIIa) respectively.
The present invention also directed to a one-pot process for the preparation of pure Valsartan substantially free from impurities of formulae (Ia), (Ib), and (Ic).